Giorgio Feroci

Solubility and solubilization properties of non-steroidal anti-inflammatory drugs

Abstract Ten non-steroidal anti-inflammatory drugs (NSAID) of the acetic and propionic classes were analyzed in the form of salts to disclose the solubilization property of their aqueous solutions toward a lipid probe (the azo-dye Orange OT). This property is related to the self-aggregation of the anions above a concentration value that differs for each drug: indomethacin and fenclofenac showed solubilization ability in the form of sodium salts in pure water (starting from 30 and 40 mM, respectively); these values decreased with increasing ionic strength. In the case of diclofenac it was necessary to use a salt prepared with an organic base, that displayed a solubility higher than that of the sodium salt, required to overcome the critical value (35 mM). Naproxen, sulindac, ketoprofen, indoprofen were used at high concentrations of their sodium salts (100–160 mM) and solubilize the dye in the presence of a high total ionic strength. Alclofenac did not display solubilization ability; fenbufen and ibuprofen were tested as salts of an organic base: results were not conclusive because the presence of the organic base in the salt form and in the solution, as added electrolyte for the ionic strength, affected the results of the solubilization tests. The results are briefly discussed in terms of hydrophilic/hydrophobic balance present on the anion of the NSAID examined, as evaluated by the fragment constant approach.

Interaction Between Trace Elements: Selenium and Cadmium Ions

The interaction between several inorganic and organic selenium-containing compounds (selenite, selenate, selenourea and selenomethionine) and Cd2+ ions was studied by polarography. The changes in polarographic currents and half-wave potentials of the metal ions as a function of the Se-derivative concentration were followed. Experimental results suggest a different behaviour depending on the oxidation state of selenium. Any interaction between selenate and Cd2+ ions can be excluded. In the case of selenite, the presence of complexes in the solution was demonstrated. The shift in the Cd2+ reduction half-wave potential when a relatively high concentration of selenourea is present indicates formation of complexes, while the decrease in limiting current reflects the limited solubility of the complex itself. Results concerning selenomethionine suggest a very weak interaction with Cd2+ ions. These preliminary results are discussed in comparison with previous findings in cellular systems and may prove helpful in understanding cadmium ion toxicity and the in vivo altered distribution of various metal ions following the administration of selenium compounds.

Interaction between indomethacin and heavy metal ions in aqueous solution

The interaction between indomethacin anions and heavy metal ions, such as cadmium, zinc and copper(II) ions, was studied in aqueous solution by polarographic techniques. Indomethacin anions form complexes with these heavy metal ions: the complex formed with cadmium ions is sparingly soluble, while more soluble and also stronger complexes are formed with zinc and copper(II). At high concentrations, where indomethacin anions undergo self-aggregation, these last compounds are solubilised. This property is briefly discussed and compared to that of bile salts. In the presence of calcium ions, indomethacin forms a poorly soluble salt and no evidence was detected for the formation of complex species.

Interaction of iron(II) with bile salts

Iron(II) ions react with small aggregates of cholate, glycocholate, chenodeoxycholate, and deoxycholate to form soluble and colloidal compounds. Taurocholate under conditions used does not react with the Fe2+ ion. Small aggregates of dihydroxy bile salts (predominating in the premicellar region, at concentrations of the bile salt above 1 mmol dm-3) have a larger affinity for Fe2+ compared to those formed from cholate anions. In their interactions with small aggregates of cholate anions, the Fe2+ ion shows an affinity comparable to that of Cu2+ and Cd2+ and somewhat larger than that of Zn2+. Small aggregates of cholate show a higher ability to mask Fe2+ than those of taurocholate and glycocholate. Interaction of glycocholic acid anions with Fe2+ ions is sufficient to prevent iron(II) precipitation.

Acidity in bile acid systems

Abstract The acidity parameter in bile acid systems was re-examined in an attempt to unify the many contrasting results reported in the literature. Discrepancies originate not only through differences in experimental approaches but mainly through the peculiar behaviour of bile acids and their salts, which can be present in aqueous solution as monomers, or simple and/or mixed aggregates. The acidity (and the pKa values) of bile acid could also be affected by parameters which do not usually play a major role (e.g. hydroxy groups, far from the reaction centre). The microenvironment, where the bile acid is partitioned (e.g. inside a mixed micelle), also makes the carboxyl group less acidic than it would commonly be, considering only structural factors. When the system is made simpler, avoiding problems of solubility and self-aggregation (e.g. in mixed solvents), unconjugated and glycine-conjugated bile acids display acidity behaviour which matches their molecular structure.

ANTIOXIDANT PROPERTIES OF BILE SALT MICELLES EVALUATED WITH DIFFERENT CHEMILUMINESCENT ASSAYS : A POSSIBLE PHYSIOLOGICAL ROLE

The antioxidant activity of a representative series of free, glycine- and taurine-conjugated bile acids was evaluated by two different chemiluminescent assays: (a) the enhanced chemiluminescence system based on horseradish peroxidase and luminol/oxidant/enhancer reagent, and (b) the hypoxanthine/xanthine oxidase/Fe(2+)-EDTA/luminol system. Bile acids were studied at final concentrations ranging from 1 to 28 mmol/L. All of the bile acids studied inhibited the steady-state chemiluminescent reaction and the extent of inhibition depended upon the structure of the bile acids, whereas the duration was related to bile acid concentration. The mechanism of the light inhibition is probably due to trapping of oxygen free radicals generated in the chemiluminescent reactions, within bile acid micelles. The free radicals trapped into micelles reduced the formation of luminol radicals and consequently the light output; when the micelles were saturated, the oxygen free radicals in solution again produced luminol radicals. The micelle interaction with reactive oxygen species could be a physiological mechanism of defence against the toxicity of those species in the intestinal content. On the other hand, alterations in bile acid organ distribution, concentration and composition leads to a membrane damage caused by their detergent-like properties, which could be associated to oxygen free radical production.

Polarographic study of the interaction of cholate aggregates with Cu2+ Pb2+ and Cd2+ ions

Abstract When the concentration of sodium cholate in a solution containing a constant concentration of a heavy metal ion (Cu2+, Cd2+, Pb2+) is gradually increased and polarographic current—voltage curves, corresponding to the reduction of the metal ion, are recorded, the observed changes in these curves can be classified into four categories. For unbuffered solutions containing 0.15 M NaNO3 and 1 × 10−4 M metal ion, these changes occur in the following ranges of cholate concentration. (1) At cholate concentrations below 1 × 10−3 M, no measurable interaction between the cholate anions and the metal ion occurs. This is indicated by the constant value of the half-wave potential and the constant height of the limiting current of the reduction wave of the metal ion. (2) For cholate concentrations between about 1 × 10−3 M and 1 × 10−2 M, complex formation, probably with small cholate aggregates, occurs, as shown by the shift of the half-wave potential of the metal ion. Some of these complexes have limited solubility, as indicated by the decrease in the limiting current of the metal ion and the turbidity of the solutions. (3) In the third range for cholate concentrations between about 1 × 10−2 and 2 × 10−2 M the current reaches its minimum value, corresponding to the solubility of the complex between the metal ion and some smaller cholate aggregates. (4) At cholate concentrations higher than about 2 × 10−2 M larger aggregates (“micelles”) are formed which solubilize the slightly soluble complexes with smaller aggregates. This is indicated by an increase in limiting current and clarification of the solution. These changes do not result from hindered transport of metal ions to the electrode surface. The complex formation involves the carboxylate group. These conclusions were reached by comparing the effect of the cholate anion with those of taurocholate and dodecyl sulfate and the same metal ions. Addition on the latter two oxysulfur anions results in a very small decrease in the limiting current of the metal ion, reflecting a limited hindrance of the transport to the electrode surface.